The present invention relates to novel noncardiotoxic compounds and pharmaceutical compositions useful in the treatment of a variety of disorders including the treatment of depression, allergies, psychoses, infection, cancer and gastrointestinal disorders. The compounds and pharmaceutical compositions of the present invention are useful in the prevention and/or reduction of severe cardiac conductance and cardiac rhythm disturbances and the cardiac arrhythmias such as torsade de pointes that lead to sudden cardiac death.
The annual incidence of sudden cardiac death is estimated to be greater than 400,000 persons in the United States alone, and accounts for approximately 50% of all deaths from cardiovascular disease (Chugh et al. Journal American College of Cardiology 44: 1268-1275 (2004); U.S. Centers for Disease Control; Chugh et al. Circulation 102:649-654 (2000)). Although the occurrence of sudden cardiac death in the general population is high, the incidence (as a percent of the total) in patients over 64 years of age and in patients with cardiovascular disease is considerably higher (Huikuri et al. New England Journal of Medicine 345(2):1473-1482 (2001); Morbidity and Mortality: 2004 Chart Book on Cardiovascular, Lung and Blood Diseases, National Institutes of Health (May 2004); and Myerburg et al. Annals of Internal Medicine 119:1187-1197 (1993)). According to the World Health Organization, the non-cardiovascular drugs most commonly associated with torsade de pointes between 1983 and 1999 are gastrointestinal, antiinfective, antidepressant, antihistaminic and antipsychotic agents. Moreover, antipsychotic, antidepressant and cardiovascular drugs account for over 40% of fatalities for all pharmaceutical agents (The 2002 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC-TESS)).
It has been reported that the incidence of sudden cardiac death is clearly associated with increasing amounts of antidepressant and antipsychotic drugs at therapeutically relevant doses (Ray, A R et al. Clinical Pharmacology and Therapeutics 75(3): 234-241 (2004); Ray, A R et al. Archives General Psychiatry 58: 1162-1167 (2001)). Although low therapeutic doses of these types of drugs (<100 mg daily) are not associated with sudden cardiac death, moderate and high therapeutic doses of these drugs (≧100 mg daily) are clearly associated with sudden cardiac death. Not only is the incidence of sudden death in patients with cardiovascular disease and treated with these drugs considerably higher than patients without cardiovascular disease, the incidence of sudden death in these patients is clearly correlated with the severity of cardiovascular disease (Ray, A R et al. Archives General Psychiatry 58: 1162-1167 (2001)).
Antipsychotics primarily antagonize central dopaminergic D2 receptor neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, α1-adrenergic, and H1-histaminergic receptors. Because antipsychotics are also are used as sedatives, as antiemetics, to control hiccups, to treat migraine headaches, and as antidotes for drug-induced psychosis, the adverse effects of antipsychotics are not confined to psychiatric patients. Antipsychotics are capable of causing orthostatic and severe hypotension, as well as prolongation of the QTc interval and QRS which can result in arrhythmias. Antipsychotics account for about 18 % of moderate (pronounced) toxicity, over 20% of life-threatening toxicity and 17% of the fatalities of all pharmaceuticals.
Tricyclic antidepressants cause the overwhelming majority of antidepressant poisoning in the United States resulting in morbidity and mortality; the most severe toxicity occurs in the cardiovascular system. Antidepressants account for about 15 % of moderate (pronounced) toxicity and 18% of life-threatening toxicity of the fatalities of all pharmaceuticals.
Antidepressants affect the prolongation of the QTc interval causing cardiotoxicity that result from direct myocardial depression, cardiac conduction disturbances, effects on peripheral vasomotor tone, and changes in the autonomic nervous system. The interactions of tricyclic antidepressants with fast sodium channels in cardiac tissue results in slowed cardiac conduction (e.g. prolonged QRS on the ECG), impaired cardiac contractility and possible ventricular dysrhythmias and inhibition of repolarization in His-Purkinje myocytes (e.g. prolonged QTc on the ECG).
Torsade de pointes is a particular cardiac problem associated with many therapeutic agents and has been implicated as a possible cause of sudden death, particularly in those individuals with a past history of disturbances of cardiac rhythm, myocardial infarction, congenital repolarization abnormalities and cardiac risk factors such as hyperlipidemia and age. This arrhythmia is a variant of paroxysmal ventricular tachycardia associated with a prolonged QTc interval or prominent U waves on the ECG. Although torsade de pointes might remit spontaneously, it is potentially lethal because it can progress to ventricular fibrillation, life-threatening arrhythmias or precipitate sudden death.
Drug-induced QTc interval prolongation may be clinically important even if the mean increase is not very large. For example, the drug terodiline was withdrawn after causing QTc interval prolongation, torsade de pointes, and sudden death. In healthy volunteers, therapeutic plasma concentrations of terodiline are associated with increases in mean QTc of only 23 ms, which are similar to the increases associated with quinidine and prenylamine. Nevertheless, much larger increases occurred in a minority of patients who developed arrhythmias. These included those predisposed by existing problems such as heart disease and congenital repolarization abnormalities. Thus, benign QTc interval prolongation in one subject may indicate that another more susceptible patient might develop extreme QTc interval prolongation and arrhythmias with the same drug at the same dose. Furthermore, small increases in QTc interval might increase the risk of ventricular fibrillation/torsade de pointes over a large population. The number of excess cases of sudden death in the large numbers of patients with minor QTc interval prolongation might actually exceed those in the small numbers of patients with extreme QTc interval prolongation. Nevertheless, the potential of a drug to cause QTc interval prolongation is currently believed to be the lower threshold of determining the cardiotoxicity of a therapeutic drug.
To date, the understanding of QTc interval prolongation has focused on defective repolarization of the heart through blockade of K+ channels, either alone or in combination with Na+ channel modulation. Prevailing theories also suggest that the arrhythmogenic potential of drugs is based on elevated plasma levels of parent drug that are not metabolized. Despite attempts to correlate the blockade of human cardiac K+ channels, such as the Herg channel, with torsade de pointes and sudden cardiac death, very little evidence exists to support this correlation. In fact, a number of severely cardiotoxic drugs that have been withdrawn from the market or denied approval by the FDA have insignificant effects on the Herg channel.
Although data has existed for decades that demonstrates adverse conductance changes and arrhythmias in patients having higher than normal plasma concentrations of drug metabolites, the cardiotoxic effects of these metabolites have received relatively little attention. These observed adverse cardiac conductance changes reflect significant changes in cardiac depolarization (QRS interval prolongation and dispersion) and atrial block (PR interval prolongation) that were correlated with elevated plasma levels of hydroxylated drug metabolites in clinical studies (Kutcher S P et al. British Journal of Psychiatry 148: 676-679 (1986); Stern S L et al. Journal of Clinical Pharmacology 11: 93-98 (1991); Vozeh S et al. American Journal of Cardiology 59: 681-684 (1987); Vozeh S et al. Clinical Pharmacology and Therapeutics 37:575-581 (1985); Drayer D E et al. Clinical Pharmacology and Therapeutics 24: 31-39 (1978)); in isolated perfused heart studies (Uematsu T et al. Archives of International Pharmacodynamics 297: 29-38 (1989); Uematsu T. et al. Journal of Pharmacological Methods 18: 179-185 (1987); and in animal studies (Pollock B G Ph.D. Dissertation University of Pittsburgh 1987; Pollack B G and Perel J M Psychopharmacology 109: 57-62 (1992); Jandhyala H S et al. European Journal of Pharmacology 42: 403-410 (1977)). Hydroxylated drug metabolites have also been reported to be responsible for severe cardiotoxic effects in vitro (Chem. Res. Toxicology (17: 623-632 (2004)).
A considerable number of cardiovascular and noncardiovascular therapeutic agents rely on secondary and tertiary amine structural motifs in their chemical structure that are responsible for their pharmacological activity. Many cardiovascular drugs, including antiarrhythmics, calcium channel antagonists, adrenergics and P-blockers contain essential secondary and tertiary amines in their chemical structure. Entire therapeutic classes of non-cardiovascular drugs, including antidepressants, antihistamines and antipsychotics rely on the secondary and tertiary amine functionality for their primary activity. Others, such as gastrointestinal and antiinfective drugs do not necessarily rely on the secondary and tertiary amine group for their primary activity; but, include this structural motif as part of their chemical structure. Cardiotoxicity associated with the therapeutic use of secondary and tertiary amine-containing drugs is reflected in a variety of cardiac disturbances, including notable changes in ECG, polymorphic ventricular tachycardia, negative inotropism, drops in blood pressure, orthostatic hypotension and depressed cardiac contractility resulting in acute cardiac arrest.
Serious cardiac arrhythmias (both fatal and non-fatal) including tachycardia, ventricular fibrillation, torsade de pointes, and QTc interval prolongation have been reported in patients taking individual secondary and tertiary amine-containing drugs that are oxidized by cytochrome P450 2D6 or combinations of secondary and tertiary amine-containing drugs that inhibit cytochrome P450 3A4. Drugs known to inhibit metabolism of secondary and tertiary amine-containing drugs by cytochrome P450 3A4 include, inter alia, ketoconazole, itraconazole, micoconazole, troleandomycin, erythromycin, fluconazole and clarithromycin. It is generally believed that inhibition of a drug's metabolism by cytochrome P450 3A4 increases the plasma concentration of the parent amine-containing drug to toxic levels; however, this view has not been supported by rigorous examination and discrimination between plasma levels of the parent drugs and their metabolites. An alternate explanation is that inhibition of cytochrome P450 3A4 by inhibitors administered concomitantly “switches” the metabolism of the parent compound from one involving both cytochrome P450 3A4 and cytochrome P450 2D6 to the metabolism of the parent drug primarily by cytochrome P450 2D6.
Cisapride (Propulsid®), shown below, was commonly used to treat nocturnal heartburn as well as a variety of other gastrointestinal disorders:

Cisapride (Propulsid®) was recently removed from the market by the FDA because of the QTc interval prolongation and life-threatening ventricular arrhythmias such as torsade de pointes which produced sudden cardiac death. These cardiotoxic effects are believed to be due to cardiac conduction delays such as the specific and potent blockade of human cardiac K+ channels, particularly the HERG channels. The specific, high affinity block of the human cardiac K+ channel HERG by cisapride (IC50 of 0.045 μM) is similar to that observed for the class III antiarrhythmic agent dofetilide (IC50 of 0.010 μM) and the nonsedating antihistamines astemizole (IC50) of 0.001 μM) and terfenadine (IC50) of 0.213 μM). It is further believed that this blockade of human cardiac K+ channels underlies the proarrhythmic effects of the drug observed under certain clinical settings. In guinea pig ventricular myocytes cisapride elicited a concentration-dependent block (IC50 of 46.9 μM) of L-type Ca2+ channels suggesting that the inhibitory effect of cisapride on calcium channels might also contribute to its cardiotoxicity under pathophysiological conditions. Cisapride is metabolized by both cytochrome P450 3A4 and cytochrome P450 2D6; however the primary metabolic route is believed to be through cytochrome P450 3A4. When higher than normal dosages of cisapride are used or with concomitant ingestion of imidazole antifungals or macrolide antibiotics, it is believed that cisapride is metabolized to cardiotoxic metabolites through aromatic hydroxylation primarily by cytochrome P450 2D6.
Astemizole (Hismanal®) and terfenadine (Seldane®) are H1 histamine antagonists that have also been removed from the market by the FDA because of QTc interval prolongation and ventricular arrhythmias such as torsade de pointes which produced sudden cardiac death.
Astemizole (Hismanal®), shown below, was commonly used to treat the symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria.

Terfenadine (Seldane®), shown below, was commonly used to symptoms associated with seasonal allergic rhinitis such as sneezing, rhinorrhea, pruritus, and lacrimation.

Astemizole (Hismanal®) and terfenadine (Seldane®) are metabolized by both cytochrome P450 3A4 and cytochrome P450 2D6, and at least astemizole is believed to be metabolized to cardiotoxic metabolites through aromatic hydroxylation. Terfenadine is believed to be metabolized to cardiotoxic metabolites primarily through aliphatic oxidation. Terfenadine and astemizole suppress the HERG current with IC50 of 0.213 μM and 0.001 μM, respectively. Clinical use of astemizole and terfenadine has been associated with hypotension, QTc interval prolongation, development of early after-depolarization, torsade de pointes, cardiac arrest and sudden death. It is believed that torsade de pointes occurs when higher than normal dosages of astemizole are used or with concomitant ingestion of imidazole antifungals or macrolide antibiotics. Concomitant administration of astemizole with ketoconazole, itraconazole, erythromycin, clarithromycin or quinine was contraindicated. It is believed that these cardiovascular effects resulting in electrocardiographic conductance defects are associated with elevation of astemizole or its metabolites in plasma. Norastemizole is 13- to 16-fold more potent as an H1 antagonist than astemizole and 20- to 40-fold more potent in inhibiting histamine-induced bronchoconstriction.
Sertindole, shown below, was an atypical antipsychotic agent commonly used for the treatment of schizophrenia outside of the United States:

In 1996, sertindole (Serlect®) was rejected by the Food and Drug Administration because it prolonged the QTc interval and was associated with a significant number of unexplained deaths in clinical trials. Sertindole had been approved in 19 European countries, but more evidence of associated arrhythmias led to its withdrawal in Europe.
In trials involving more than 2,000 patients up to June 27, 1996 patients died while receiving sertindole, including 13 sudden deaths. Although there was no proof that the drug actually caused these deaths, sertindole was known to induce QT interval prolongation in some patients. Other antipsychotics have been associated with QT interval prolongation, and sudden death has been associated with schizophrenia.
Secondary and tertiary amines and other drug substrates for the P450 2D6 isozymes are lipophilic compounds that posses a planar component and are strong organic bases that are protonated at physiological pH. It is believed that a charged nitrogen atom on these amines is required to orient the drug correctly within the P450 2D6 active site where metabolic oxidation occurs. At this site, it is believed that the secondary or tertiary amine molecule adopts a conformation in which the positively-charged nitrogen (N+) atom is oriented towards an anionic location (COO−) on the P450 2D6 protein while the aromatic ring is aligned with a relatively planar, hydrophobic region of the protein. It is believed that when this conformation is adopted the nitrogen atom and the metabolic oxidation are in close proximity and metabolism of the drug occurs. Although cytochrome P450 3A4 is located both in the liver and the intestine, P450 2D6 is located in the liver and not the intestine.
Metabolic oxidation of drugs and other xenobiotic substances is a first step in a biotransformation that the body relies on to distribute active drug metabolites to tissues and also to eliminate them from the body. In some cases, this metabolic oxidation involves the formation of a pharmacologically active metabolite, and in other cases it involves the formation of hydroxylated metabolites through oxidation of an aromatic ring. Although metabolic oxidation to pharmacologically active metabolites is essential, metabolism of secondary and tertiary amine-containing drugs to hydroxymetabolites by cytochrome P450 2D6 and cytochrome P450 3A4 has serious cardiotoxicity implications to patients, particularly at high oral doses. We have found that the hydroxymetabolites are primarily responsible for the cardiotoxicity and not the parent secondary and tertiary amine-containing drugs. Published studies in humans (Dencker H et al. Clinical Pharmacology and Therapeutics 19: 584-586 (1976)) have also shown that the concentration of the tertiary-amine drugs is highest after leaving the liver and immediately prior to reaching the heart (8-10 times the concentration in the systemic circulation). Consequently, a patient is at highest risk during the first-pass metabolism of the secondary and tertiary amine drugs when the concentration of the cardiotoxic hydroxymetabolites is highest.
Published studies in humans (Gram L F and Christiansen J Clinical Pharmacology and Therapeutics 17: 555-563 (1975) have further shown that the concentration of the hydroxymetabolites of imipramine in plasma reaches significantly higher levels that the parent compounds or their active metabolites.
Likewise, published studies (Segura M et al. Rapid Communications in Mass Spectrometry 17: 1455-1461 (2003)) report that the concentration of the hydroxymetabolites of paroxetine in human plasma reaches significantly higher levels that the parent compounds or their active metabolites.
Adapted fromSegura et al. 2003Ratio ofHydroxylatedMetabolite toParoxetineMetaboliteParoxetineCmax (ug/L) 8.60 92.4010.7Tmax (hours)5 (3-5)3 (3-5)—AUC(0-24) (ug/L/h)96.50988.1010.2
Consequently, a patient is at greatest risk during the first-pass metabolism of the secondary and tertiary amine drugs when the concentration of the cardiotoxic hydroxymetabolites is highest. We believe that reventing metabolism of secondary and tertiary amine-containing drugs to hydroxymetabolites by cytochrome P450 2D6 and cytochrome P450 3A4 important to reducing their cardiotoxicity.
Inhibition studies on a series of imipramine analogs were conducted and the analogs tested for CYP2D6 activity, the enzyme that is responsible for the formation of the cardiotoxic hydroxylated metabolites (Halliday R C et al. European Journal of Drug Metabolism and Pharmacokinetics 22: 291-294 (1997)). The analogs of imipramine that were tested were designed to have the positively charged nitrogen atom removed from the active site of CYP2D6. The three approaches were adjustment of alkyl chain length, alkyl bond rigidity (restricted bond rotation) and removing the positive charge on the tertiary nitrogen atom using the prodrug imipramine-N-oxide. Halliday et al. reported that removal of the positively charged nitrogen atom of imipramine from the active site of CYP2D6 either by lengthening the alkyl chain length or altering the pKa of imipramine with using imipramine-N-oxide abolished the metabolism of imipramine by CYP2D6 to the hydroxymetabolite.
A considerable amount of preclinical and clinical data is available that demonstrates that imipramine-N-oxide is not subject to first-pass metabolism or aromatic hydroxylation to the cardiotoxic hydroxymetabolites by cytochrome P450 2D6 and cytochrome P450 3A4. This prodrug is rapidly converted in the systemic circulation to imipramine which is then metabolized under much lower systemic plasma concentrations to the active form (desipramine) and hydroxylated metabolites that are not as likely to produce severe cardiotoxicity. In published preclinical and clinical studies imipramine-N-oxide has been shown not produce the cardiotoxicity of the tertiary amine drug imipramine. Nevertheless, formulation difficulties and the complexities of imipramine-N-oxide metabolism in plasma limits its use.
It is believed, in accordance with the present invention that the piperidine chemical group with its tertiary amine in cisapride, astemizole, sertindole, trazadone, nefazadone, buspirone and terfenadine contributes to cardiac conduction disturbances and orientation of the drugs within the binding sites of the cytochrome enzymes responsible for the responsible metabolism of these drugs by aromatic or cycloalkyl hydroxylation.

It is further believed that the chemically related piperazine chemical group with its tertiary amine contributes to cardiac conduction disturbances and orientation of the drugs within the binding sites of the cytochrome enzymes responsible for the responsible metabolism of these drugs by for aromatic or cycloalkyl hydroxylation. Pharmacologic agents containing a piperazine group known to cause cardiac conduction disturbances include buclizine, buspirone, cyclizine, doxazosin, fluphenazine, gepirone, hydroxyzine, itraconazole, ketoconazole, loxapine, meclizine, olanzapine, perphenazine, quetiapine, trazadone, nefazadone and ziprasidone. By way of example, the chemical structures of a series of pharmacological compounds containing a piperazine moiety and having antihistamine activity are shown below:

Fluoroquinolone antibiotics are pharmacologic agents containing a piperazine group known to cause serious cardiac conduction disturbances and torsade de pointes. Fluoroquinolone antibiotics approved for marketing and having a secondary amine on the piperazine ring include norfloxacin, lomefloxacin, ciprofloxacin, enoxacin, gatifloxacin, sparfloxacin, temafloxacin, grepafloxacin and moxifloxacin. Several of these fluoroquinolone agents have already been removed from the market because of life-threatening cardiac conduction disturbance or torsade de pointes. By way of example, the chemical structures of a series of fluoroquinolone compounds containing a secondary amine on the piperazine moiety are shown below:

Fluoroquinolone antibiotics approved for marketing and having a secondary amine on the piperidine ring include moxifloxacin as shown below:

It is therefore an object of the present invention to provide non-cardiotoxic pharmacologically active compounds having modulated cytochrome P 450 metabolism.
It is a further object of the invention to provide non-cardiotoxic pharmacologically active compounds having reduced metabolism by cytochrome P450 2D6.
It is a further object of the invention is to provide non-cardiotoxic prodrugs of pharmacologically active compounds having modulated cytochrome P 450 metabolism.
It is a further object of the invention to provide non-cardiotoxic pharmacologically active compounds having reduced metabolism by cytochrome P450 2D6 and cytochrome P450 3A4.
A further object of the invention is to provide non-cardiotoxic prodrugs that will modify the physicochemical properties of tertiary amine-containing drugs such that these drugs will exhibit reduced binding to the CYP2D6 metabolizing enzymes during first-pass absorption.
A further object of the invention is to provide non-cardiotoxic prodrugs that can be hydrolyzed in the plasma after absorption and be converted directly to the therapeutically active form of the parent compounds.
A further object of the invention is to provide non-cardiotoxic prodrugs that lower the pKa of the tertiary amine group to a level such that the majority of the tertiary amine is uncharged at physiological pH (pH 7.4). For example, imipramine has pKa of 9.5 and is completely ionized as it is transported through the gastrointestinal tract. After oral ingestion, imipramine is rapidly and completely absorbed from the small intestine, with peak plasma concentration within two to five hours. Imipramine is subject to extensive first-pass metabolism in the liver, and is eliminated by demethylation to the active metabolite, desipramine and to a lesser extent by aromatic hydroxylation to 2-hydroxyipramine. Desipramine, in turn, is metabolized by aromatic hydroxylation to 2-hydroxydesipramine. The systemic availability of imipramine in healthy subjects ranges from 27% to 80% and the corresponding first-pass metabolism ranges from 20% to 73%. Imipramine-N-oxide, a nitrogen-atom prodrug of imipramine which has a pKa of about 4.7, has a systemic availability of about 100% after oral administration suggesting that there is no first pass effect. Both preclinical and clinical studies have shown that the cardiotoxicity of imipramine-N-oxide is significantly reduced over that of imipramine.